High rates of relapse to drug use after prolonged drug-free periods characterize the behavior of experienced heroin and cocaine users. The behavioral and neurochemical events that contribute to these high rates, however, are not well understood. Relapse can be induced in human subjects and laboratory animals by reexposure to the drug previously used, reexposure to environmental cues paired with drug self-administration, and by exposure to environmental stressors. We are using an animal model of relapse, a reinstatement model, to study brain systems and neurotransmitters involved in relapse induced by environmental stressors, conditioned drug cues and drug reexposure in heroin- and cocaine-experienced rats after prolonged drug-free periods. During the last year, we continued to study the molecular mechanisms underlying the time-dependent changes in responsiveness to cocaine-associated cues after withdrawal from the drug. The main finding of this line of research is the identification of amygdala ERK signalling pathway as a key modulator of cocaine seeking after withdrawal. In other studies we have found that glutamate in the ventral tegmental area and the nucleus accumbens is a key modulator of context-inudced reinstatement of heroin seeking. We also have found that the drug yohimbine, which induces anxiety-like responses in humans, reinstates palatable food-seeking behavior in rats after prolonged withdrawal periods.